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Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects

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Abstract

Rationale

Some of the behavioral consequences of deficits in N-methyl-d-aspartate (NMDA) glutamate receptor function are thought to arise from the disinhibition of cortical glutamatergic circuitry.

Objective

This study evaluated whether pretreatment with a drug that reduces glutamatergic activation, the group II metabotropic glutamate receptor (mGluR) agonist, LY354740, reduced the cognitive effects of the NMDA glutamate receptor antagonist, ketamine, in healthy human subjects.

Methods

Nineteen healthy human subjects completed 3 test days during which LY354740 (matched placebo, 100 mg, 400 mg) was administered under double-blind conditions 4 h prior to the single-blind intravenous administration of saline and 5.7 h prior to ketamine administration (bolus of 0.26 mg/kg over 1 min, infusion of 0.65 mg/kg per hour for 100 min). Thus on each test day each subject received a single dose of LY354740 (or its matched placebo) and both saline and ketamine infusions.

Results

Ketamine impaired attention, working memory, and delayed recall. It also produced positive and negative symptoms, perceptual changes, and dysphoric mood. LY354740 did not have a significant effect on working memory on the placebo day; however, it produced a significant dose-related improvement in working memory during ketamine infusion.

Conclusions

These data provide preliminary and suggestive evidence that LY354740 or other group II mGluR agonists might play a role in treating working memory impairment related to deficits in NMDA receptor function.

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Acknowledgements

The authors thank the Eli Lilly and Company for the provision of LY354740 and administrative and scientific support of the study. The authors also acknowledge support from NARSAD (W.A.S.), the Department of Veterans Affairs (Alcohol Research Center, Schizophrenia Biological Research Center, National Center for PTSD), the National Institute of Mental Health (5P50 MH44866-12), and the National Institute on Alcohol Abuse and Alcoholism (KO5 AA 014906-01). The authors thank Dr. Everett J. Perkins for input regarding the analysis of plasma levels of LY354740. The authors also thank Angelina Genovese, RN, and the Nursing Staff of the Biological Studies Unit of the VA Connecticut Healthcare System, West Haven, Conn. and Deborah Mordowanic, RN, and the Nursing Staff of the Clinical Neuroscience Research Unit of the Abraham Ribicoff Research Facilities of the Connecticut Mental Health Center, New Haven, Conn. for their central contributions to the success of this project. Lastly, the authors thank Bita Moghaddam, PhD, for sharing her experience with LY354740 and NMDA receptor antagonists in animals with the authors.

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Correspondence to John H. Krystal.

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Krystal, J.H., Abi-Saab, W., Perry, E. et al. Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology 179, 303–309 (2005). https://doi.org/10.1007/s00213-004-1982-8

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  • DOI: https://doi.org/10.1007/s00213-004-1982-8

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